Barreto Gamarra, Carlos A.

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    Development of integrin-guided substrates to support cardiac cell manufacturing applications
    (2022-07-08) Barreto Gamarra, Carlos A.; Domenech, Maribella; College of Engineering; Ortiz Bermudez, Patricia; Torres Lugo, Madeline; Department of Chemical Engineering; Rúa De la Asunción, Armando
    Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a potential cell therapy due to their ability to recover contractile function after myocardial infarction. Despite their therapeutic potential manufacture barriers have limited their progress towards pre-clinical assays Current standard methods have inconsistent cardiac cell yields and low maturation levels which increases the number of viable cells needed per dose. Also, transferred differentiated cells have reported low cell attachment levels (<60%) and viability (<70%) which further impairs achieving high therapeutic potency. In tissues, changes of the extracellular matrix (ECM) guide the differentiation and maturation process during cardiac development. The evolution of the ECM is accompanied with shifts in the integrin expression levels suggesting that ECM-integrin interactions are key mediators of cardiac cell differentiation and potency. Given the known role of integrins in supporting cell adhesion and survival, it is hypothesized that the use of ECM components tuned with the integrin expression in differentiating cardiac cells will improve cell maturation and recovery during the cell manufacture process. In this study, the integrin expression profile was mapped across the cardiac cell differentiation stages to identify ECM components for examination of cardiac cell yields and potency. WTC-11 hiPSCs were cultured in selected combinations of ECM proteins at different stages of cardiac development for examination of cardiac cell yields and potency or cultured as differentiated cells in suspension with selected media supplements for assessment of cell survival and recovery. Results showed that integrins associated to RGD-rich components were favored during early differentiation and integrins associated to collagen I were more prominent at the cardiac progenitor and differentiated stages. The sequential use of Vitronectin during early differentiation followed by collagen I at the progenitor stage significantly increased cTNT and cTNI cell yields by 2 and 3 folds respectively compared to the standard method in Matrigel®. Also, the use of Collagen I and non-cell adherent media supplements were found to maintain viability levels above 70% for up to 5 days in ambient temperature. This study supports the potential of ECM-integrin-guided substrates in guiding the cardiac cell differentiation, maturation, and recovery process for cell manufacturing applications.